Mechanisms by which CD8 T cells shape CNS autoimmunity initiated by CD4 T cells

描述（由申请人提供）：多发性硬化症（MS）是一种破坏性的中枢神经系统（CNS）脱髓鞘疾病，是年轻人神经功能障碍的主要原因。自反应性髓鞘特异性T细胞被认为启动MS并在整个疾病过程中发挥突出的致病作用。开发MS的治疗方法一直具有挑战性，部分原因是在炎性浸润、病变和临床病程中观察到的异质性表明，特定致病机制的相对贡献可能在个体患者中有所不同。这种异质性可能反映了募集到CNS的效应细胞类型的个体差异，这些效应细胞诱导组织分化。 通过不同的机制造成损害。另一个复杂性水平是由于组织内的炎症环境是动态的，并且将反映具有不同活性的特异性T细胞亚群的相对丰度。因此，更好地了解不同T细胞亚群在相同微环境中的活性如何相互影响，以及它们与CNS驻留细胞的相互作用如何共同传播炎症并诱导组织损伤，对于开发有效的治疗干预至关重要。CD 4+髓鞘特异性T细胞在MS和实验性自身免疫性脑脊髓炎（EAE）动物模型中的作用已被广泛研究。两种CD 4+效应T细胞亚群，IFN-？-产生Th 1细胞和产生IL-17的Th 17细胞参与MS的发病机制，并且这些亚群在EAE的中枢神经系统（CNS）内诱导不同的炎症模式。CD 8+髓鞘特异性T细胞的作用尚未得到充分研究，尽管大量数据暗示了CD 8 + T细胞在MS中的作用。很少有模型被开发来研究CD 8 + T细胞在MS中的作用，因此关于该T细胞亚群如何影响疾病过程知之甚少。本申请提出使用新开发的工具来研究CD 8+髓鞘特异性T细胞影响由CD 4 + T细胞引发的EAE的机制。我们的基本假设是髓鞘特异性CD 8 + T细胞在由CD 4 + T细胞引发的疾病期间被募集到CNS，并且CD 4+和CD 8 + T细胞的同时但不同的活动决定了病变形成、组织损伤和临床体征的模式。提出了三个目标来验证这一假设：1。确定髓磷脂特异性CD 8 + T细胞的重新表达如何改变由CD 4 + T细胞诱导的急性和慢性EAE的过程。 2：定义在CD 4 T细胞引发的EAE期间，由重新接种到CNS的CD 8 + T细胞获得的免疫功能。 3：确定髓磷脂特异性CD 8 + T细胞对由Th 1相对于Th 17细胞诱导的CNS自身免疫的影响。

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a devastating, demyelinating disease of the central nervous system (CNS) and is the leading cause of neurological disability in young adults. Self-reactive myelin-specific T cells are believed to initiate MS and to play a prominent pathogenic role throughout the course of disease. Developing therapies for MS has been challenging, in part because the heterogeneity seen in inflammatory infiltrates, lesions and clinical course suggest that the relative contribution of specific pathogenic mechanisms may vary among individual patients. This heterogeneity may reflect individual variation in the types of effector cells recruited to the CNS that induce tissue damage via distinct mechanisms. An additional level of complexity arises from the fact that the inflammatory milieu within the tissue is dynamic and will reflect the relative abundance of specific T cells subsets with different activities. Thus, a better understanding of how the activit of distinct T cell subsets in the same microenvironment influence each other and how their interactions with CNS resident cells act in concert to promulgate inflammation and induce tissue damage, is essential to develop effective therapeutic intervention. The role of CD4+ myelin-specific T cells has been extensively studied in MS and the animal model experimental autoimmune encephalomyelitis (EAE). Two CD4+ effector T cell subsets, IFN-?- producing Th1 cells and IL-17-producing Th17 cells, have been implicated in the pathogenesis of MS, and these subsets induce different inflammatory patterns within the central nervous system (CNS) in EAE. The role of CD8+ myelin-specific T cells has not been well-studied, even though a large body of data implicates a role for CD8+ T cells in MS. Few models have been developed to study the role of CD8+ T cells in MS, therefore little is known about how this T cell subset influences the disease process. This application proposes to use newly developed tools to investigate the mechanisms by which CD8+ myelin-specific T cells influence EAE initiated by CD4+ T cells. Our fundamental hypothesis is that myelin-specific CD8+ T cells are recruited to the CNS during disease initiated by CD4+ T cells, and that the simultaneous, but distinct, activities of CD4+ and CD8+ T cells determine the pattern of lesion formation, tissue damage and clinical signs. Three aims are proposed to test this hypothesis: 1. DETERMINE HOW RECRUITMENT OF MYELIN-SPECIFIC CD8+ T CELLS MODIFIES THE COURSE OF ACUTE AND CHRONIC EAE INDUCED BY CD4+ T CELLS. 2: DEFINE THE EFFECTOR FUNCTIONS ACQUIRED BY CD8+ T CELLS RECRUITED TO THE CNS DURING CD4 T CELL-INITIATED EAE. 3: DETERMINE THE INFLUENCE OF MYELIN-SPECIFIC CD8+ T CELLS ON CNS AUTOIMMUNITY INDUCED BY TH1 VERSUS TH17 CELLS.